A GRAIN of SAND for DUNE: Development of simulations and reconstruction algorithms for the liquid Argon target of the SAND detector in DUNE

Neutrinos are the most abundant of known matter particles in the Universe and the study of their properties has produced many surprises, including the evidence for physics beyond the Standard Model of particle physics. In particular, the phenomenon of neutrino oscillations, transitions in flight between the different types of neutrinos, provides compelling evidence that neutrinos have small, but non-zero, masses and that their mass states are mixtures of their flavor states. The field of neutrino physics has advanced rapidly and there is currently a good understanding of most experimental results in the context of neutrino oscillations. Presently, the focus of current and future experiments has therefore shifted to making precise measurements of the oscillation parameters and trying to understand the nature of neutrino masses. The Deep Underground Neutrino Experiment (DUNE) is a future neutrino oscillation experiment that is designed to achieve the sensitivity required to finally solve long-standing open questions in neutrino physics, such as finding the ordering of neutrino mass states and measuring the possible matter-antimatter asymmetry in this sector of the Standard Model. The latter would be a very important step in our understanding of the Universe: current observations show in fact a large asymmetry, with matter strongly dominating over antimatter from the small to the large structures of the cosmos, despite our cosmological models predicting that the Big Bang should have created equal amounts of matter and antimatter. If an intrinsic asymmetry exists within the laws of physics, it would explain why the balance was broken in favor of matter, rather than antimatter. A small asymmetry has already been found in the quark sector of the Standard Model, but it is still not sufficient to explain the observations. A precise measurement of the same effect in the neutrino sector is therefore crucial. DUNE will be employing a high-intensity neutrino beam produced at the Fermi National Accelerator Laboratory (Fermilab) in Illinois (US) and directed towards an underground detector at the Sanford Underground Research Facility (SURF) in South Dakota (US). Neutrino oscillations are measured by comparing recorded neutrino events between two detectors at the near and far sites. The Far Detector will consist of a modular 68 kt liquid argon time projection chamber, by far the largest liquid argon neutrino detector ever built. Neutrinos cannot be detected directly, but charged articles resulting from their interactions in liquid argon produce two signals, vacuum ultraviolet (VUV) light from the excitation of Ar atoms and electric charge from their ionization. Both these signals are collected and used to achieve a complete reconstruction of the neutrino interaction. The Near Detector will instead be a suite of three detectors, as it needs to address some of the most important challenges of the experiment. Apart from characterizing the unoscillated neutrino beam, the precision needed to achieve DUNE goals requires to carefully constrain the systematic uncertainties of the measurement. The Near Detector is therefore expected to fulfill this task by providing corrections for extrapolating the beam to the far site, measuring ν-Ar cross-sections and tuning the interaction models. SAND (System for on-Axis Neutrino Detection) will be one of the three components of the Near Detector complex, acting as the primary beam monitor of the experiment. It will be a magnetized detector, equipped with a high resolution tracker to measure the momentum of particles by their curvature and a high performance electromagnetic calorimeter. Moreover, it will also host several different targets to study neutrino interactions on different nuclei. In particular, since the presence of Ar targets in the Near Detector is essential for comparison with the Far Detector, SAND will contain a small (1 t) liquid argon cryostat inside its magnetic volume called GRAIN (Granular Argon for Interaction of Neutrinos). GRAIN is not foreseen simply as a passive target, but it will also be instrumented to actively contribute to the reconstruction of neutrino interactions occurring inside. In principle, liquid argon provides information via scintillation light and ionization charge. However, given the high rate environment and the shape of the cryostat, collecting ionization charge as it is done in the Far Detector will not be feasible. On the other hand, equipping GRAIN with photodetectors only will allow to measure the total energy released in the medium and give a time reference to the event, but the spatial reconstruction ability would still be limited. The proposed improvement to recover the spatial reconstruction is to place imaging devices on the inner walls of GRAIN to take pictures of neutrino interactions. Such devices are an innovative concept for liquid argon detectors, as scintillation light has never been exploited to this extent. Since the VUV wavelength and the cryogenic environment rule out commercially available cameras, a custom-made solution is being pursued. The active photosensor will be a 2D array of Silicon PhotoMultipliers (SiPMs), each acting as an independent pixel, while two technologies are currently being investigated for the imaging element of the camera: coded aperture masks and lenses. The purpose of this thesis has been the study of the lens-based option and its performance for the reconstruction of ν-Ar interactions in SAND. An optimized device was designed to address the challenges derived from operating in liquid argon and validated using Monte Carlo simulations, leading to the definition of a preliminary geometrical configuration of these cameras in GRAIN. An optical simulation of GRAIN was then developed to simulate its response to neutrino interactions within the SAND framework. This software package includes a full description of the scintillation mechanism and light propagation, returning as output the set of images recorded by each camera. A preliminary reconstruction algorithm was also developed to analyze these 2D images and combine them together to obtain a 3D reconstruction of the event. The overall reconstruction performance was then studied by integrating together information coming from all SAND subsystems. In addition to the simulation efforts, the first camera prototype was built and tested in a warm environment, showing agreement with the expectations, while cold tests are in preparation for the near future. Despite more development being needed, this innovative optical readout for GRAIN is expected to provide a significant contribution to the selection of ν-Ar samples and the fulfillment of the Near Detector goals

Indoor air pollution impacts cardiovascular autonomic control during sleep and the inflammatory profile

The present study explores the modifications of cardiovascular autonomic control (CAC) during wake and sleep time and the systemic inflammatory profile associated with exposure to indoor air pollution (IAP) in a cohort of healthy subjects. Twenty healthy volunteers were enrolled. Indoor levels of fine particulate matter (PM2.5), nitrogen dioxide (NO2) and volatile organic compounds (VOCs) were monitored using a portable detector for 7 days. Together, a 7-day monitoring was performed through a wireless patch that continuously recorded electrocardiogram, respiratory activity and actigraphy. Indexes of CAC during wake and sleep time were derived from the biosignals: heart rate and low-frequency to high-frequency ratio (LF/HF), index of sympathovagal balance with higher values corresponding to a predominance of the sympathetic branch. Cyclic variation of heart rate index (CVHRI events/hour) during sleep, a proxy for the evaluation of sleep apnea, was assessed for each night. After the monitoring, blood samples were collected to assess the inflammatory profile. Regression and correlation analyses were performed. A positive association between VOC exposure and the CVHRI (Δ% = +0.2% for 1 μg/m3 VOCs, p = 0.008) was found. The CVHRI was also positively associated with LF/HF during sleep, thus higher CVHRI values corresponded to a shift of the sympathovagal balance towards a sympathetic predominance (r = 0.52; p = 0.018). NO2 exposure was positively associated with both the pro-inflammatory biomarker TREM-1 and the anti-inflammatory biomarker IL-10 (Δ% = +1.2% and Δ% = +2.4%, for 1 μg/m3 NO2; p = 0.005 and p = 0.022, respectively). The study highlights a possible causal relationship between IAP exposure and higher risk of sleep apnea events, associated with impaired CAC during sleep, and a pro-inflammatory state counterbalanced by an increased anti-inflammatory response in healthy subjects. This process may be disrupted in vulnerable populations, leading to a harmful chronic pro-inflammatory profile. Thus, IAP may emerge as a critical and often neglected risk factor for the public health that can be addressed through targeted preventive interventions

A General Strategy to Endow Natural Fusion-protein-Derived Peptides with Potent Antiviral Activity

Fusion between the viral and target cell membranes is an obligatory step for the infectivity of all enveloped virus, and blocking this process is a clinically validated therapeutic strategy

The role of immune suppression in COVID-19 hospitalization: clinical and epidemiological trends over three years of SARS-CoV-2 epidemic

Specific immune suppression types have been associated with a greater risk of severe COVID-19 disease and death. We analyzed data from patients >17 years that were hospitalized for COVID-19 at the “Fondazione IRCCS Ca′ Granda Ospedale Maggiore Policlinico” in Milan (Lombardy, Northern Italy). The study included 1727 SARS-CoV-2-positive patients (1,131 males, median age of 65 years) hospitalized between February 2020 and November 2022. Of these, 321 (18.6%, CI: 16.8–20.4%) had at least one condition defining immune suppression. Immune suppressed subjects were more likely to have other co-morbidities (80.4% vs. 69.8%, p < 0.001) and be vaccinated (37% vs. 12.7%, p < 0.001). We evaluated the contribution of immune suppression to hospitalization during the various stages of the epidemic and investigated whether immune suppression contributed to severe outcomes and death, also considering the vaccination status of the patients. The proportion of immune suppressed patients among all hospitalizations (initially stable at <20%) started to increase around December 2021, and remained high (30–50%). This change coincided with an increase in the proportions of older patients and patients with co-morbidities and with a decrease in the proportion of patients with severe outcomes. Vaccinated patients showed a lower proportion of severe outcomes; among non-vaccinated patients, severe outcomes were more common in immune suppressed individuals. Immune suppression was a significant predictor of severe outcomes, after adjusting for age, sex, co-morbidities, period of hospitalization, and vaccination status (OR: 1.64; 95% CI: 1.23–2.19), while vaccination was a protective factor (OR: 0.31; 95% IC: 0.20–0.47). However, after November 2021, differences in disease outcomes between vaccinated and non-vaccinated groups (for both immune suppressed and immune competent subjects) disappeared. Since December 2021, the spread of the less virulent Omicron variant and an overall higher level of induced and/or natural immunity likely contributed to the observed shift in hospitalized patient characteristics. Nonetheless, vaccination against SARS-CoV-2, likely in combination with naturally acquired immunity, effectively reduced severe outcomes in both immune competent (73.9% vs. 48.2%, p < 0.001) and immune suppressed (66.4% vs. 35.2%, p < 0.001) patients, confirming previous observations about the value of the vaccine in preventing serious disease

Teaching NeuroImages: Brain MRI and DaT-SPECT imaging in adult GM1 gangliosidosis

[no abstract available

A novel STING variant triggers endothelial toxicity and SAVI disease

: Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report and characterize a novel STING variant (F269S) identified in a SAVI patient. Single-cell transcriptomics of patient bone marrow revealed spontaneous activation of interferon (IFN) and inflammatory pathways across cell types and a striking prevalence of circulating naïve T cells was observed. Inducible STING F269S expression conferred enhanced signaling through ligand-independent translocation of the protein to the Golgi, protecting cells from viral infections but preventing their efficient immune priming. Additionally, endothelial cell activation was promoted and further exacerbated by cytokine secretion by SAVI immune cells, resulting in inflammation and endothelial damage. Our findings identify STING F269S mutation as a novel pathogenic variant causing SAVI, highlight the importance of the crosstalk between endothelial and immune cells in the context of lung disease, and contribute to a better understanding of how aberrant STING activation can cause pathology

Left Heart Disease Phenotype in Elderly Patients with Pulmonary Arterial Hypertension: Insights from the Italian PATRIARCA Registry

Pulmonary arterial hypertension (PAH) in the elderly is often associated with left heart disease (LHD), prompting concerns about the use of pulmonary vasodilators. The PATRIARCA registry enrolled ≥70 year-old PAH or chronic thromboembolic pulmonary hypertension (CTEPH) patients at 11 Italian centers from 1 December 2019 through 15 September 2022. After excluding those with CTEPH, post-capillary PH at the diagnostic right heart catheterization (RHC), and/or incomplete data, 23 (33%) of a total of 69 subjects met the criteria proposed in the AMBITION trial to suspect LHD. Diabetes [9 (39%) vs. 6 (13%), p = 0.01] and chronic kidney disease [14 (61%) vs. 12 (26%), p = 0.003] were more common, and the last RHC pulmonary artery wedge pressure [14 ± 5 vs. 10 ± 3 mmHg, p p = 0.02] was lower in LHD than non-LHD patients. However, PAH therapy was similar, with 13 (57%) and 23 (50%) subjects, respectively, taking two oral drugs. PAH medication patterns remained comparable between LHD and non-LHD patients also when the former [37, 54%] were identified by atrial fibrillation and echocardiographic features of LHD, in addition to the AMBITION criteria. In this real-world snapshot, elderly PAH patients were treated with pulmonary vasodilators, including combinations, despite a remarkable prevalence of a LHD phenotype

Inhibition of Nipah virus envelope glycoproteins mediated fusion by the HPIV-3 HRC-derived fusion inhibitors HPIV-P2 (○), the monomeric cholesterol-tagged fusion inhibitor HPIV-P3 (•), the dimeric fusion inhibitor HPIV-P5 (□), and the dimeric cholesterol-tagged inhibitor HPIV-P4 (▪).

<p>The percent inhibition of fusion (compared to control cells not treated with peptide) is shown as a function of the (log-scale) concentration of peptide. The values are means (±SD) of the results from three experiments.</p